Professional Documents
Culture Documents
Prepared for:
ECITA (EU) Ltd.
92 New Road,
Skewen
Neath Port Talbot
SA10 6HG
Prepared by:
Peter Watts
SB/BTS and EUROTOX Registered Toxicologist
Signature: ...................................................................................
TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................................................................... 2
INTRODUCTION .............................................................................................................................................................. 3
KEY LEGISLATIVE REFERENCES....................................................................................................................................... 3
HARMONISED ACUTE TOXICITY CLASSIFICATION OF NICOTINE (SUBSTANCE)........................................................... 4
Acute oral toxicity ...................................................................................................................................................... 4
Acute dermal toxicity ................................................................................................................................................. 4
ACUTE ORAL AND DERMAL TOXICITY VALUES FOR NICOTINE .................................................................................... 4
Summary of acute oral lethal values ......................................................................................................................... 4
Summary of acute dermal lethal values ................................................................................................................... 4
Tabulated acute oral lethal studies ........................................................................................................................... 5
Tabulated acute dermal lethal studies ..................................................................................................................... 6
SELECTION OF KEY LD50 VALUES FOR MIXTURE CLASSIFICATION .............................................................................. 7
CLASSIFICATION OF NICOTINE MIXTURES .................................................................................................................... 8
Acute oral classification ............................................................................................................................................. 9
Acute dermal classification ........................................................................................................................................ 9
NOTE ............................................................................................................................................................................. 10
REFERENCES ................................................................................................................................................................. 10
June 2014
INTRODUCTION
Bibra was asked for independent advice on the appropriate EU classification of mixtures containing
nicotine, for acute toxicity by the oral and dermal exposure routes. The client asked that the
classification be carried out according to current EU legislation as laid down in EU Regulation
1272/2008, as amended. In particular, the client asked about the concentration-related category
transitions for nicotine mixtures (where the other components were not acutely toxic).
Regulation 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of
substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation 1907/2006. Official
Journal of the European Union L353, 1-1355 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:en:PDF.
2
Commission Regulation (EC) 790/2009 of 10 August 2009 amending, for the purposes of its adaptation to technical and scientific progress,
Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and
mixtures http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:235:0001:0439:en:PDF
3
Commission Regulation (EU) No 286/2011 of 10 March 2011 amending, for the purposes of its adaptation to technical and scientific
progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of
substances and mixtures (Text with EEA relevance). http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:083:0001:0053:en:PDF
4
Commission Regulation (EU) No 618/2012 of 10 July 2012 amending, for the purposes of its adaptation to technical and scientific progress,
Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and
mixtures (Text with EEA relevance). http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:179:0003:0010:EN:PDF
5
Commission Regulation (EU) No 487/2013 of 8 May 2013 amending, for the purposes of its adaptation to technical and scientific progress,
Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and
mixtures (Text with EEA relevance). http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:149:0001:0059:EN:PDF
6
Commission Regulation (EU) No 944/2013 of 2 October 2013 amending, for the purposes of its adaptation to technical and scientific
progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of
substances and mixtures (Text with EEA relevance). http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:261:0005:0022:EN:PDF#!
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Commission Regulation (EU) No 758/2013 of 7 August 2013 correcting Annex VI to Regulation (EC) No 1272/2008 of the European
Parliament and of the Council on classification, labelling and packaging of substances and mixtures (Text with EEA relevance). http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:216:0001:0058:EN:PDF
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Consolidated version: Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification,
labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending
Regulation (EC) No 1907/2006 (Text with EEA relevance) as amended by Regulations EC 790/2009 and EU 286/2011. http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2008R1272:20110419:EN:PDF
June 2014
June 2014
et al. 1994). In cats, doses of about 66-100 mg/kg bw caused clinical toxicity (vomiting, CNS effects
and deaths (Travell, 1960).
LD50
Reference
3.3 mg/kg bw
16 mg/kg bw
LD50 study
24 mg/kg bw
LD50 study
50-60 mg/kg
bw
Trochimowicz et al.
1994
LD50 study
50 mg/kg bw
Sine, 1993
LD50 study
50-60 mg/kg
bw
Trochimowicz et al.
1994
53 mg/kg bw
70-71 mg/kg
bw
Rat, Sprague-
75 mg/kg bw
June 2014
LD50
Reference
83 mg/kg bw
Gaines, 1960
LD50 study
188 mg/kg bw
LD50
Reference
140 mg/kg bw
Trochimowicz et al.
1994
285 mg/kg bw
Gaines, 1960
>360 mg/kg
bw
[no deaths
were seen]
LD50 study
50 mg/kg bw
Trochimowicz et al.
1994
LD50 study
140 mg/kg bw
UK PSD, 2008
The nicotine
base produced
overt CNS
toxicity,
vomiting, and
17/21 cats
died in 21-195
Travell, 1960
June 2014
LD50
Reference
min.
The sulphate
caused milder
effects and all
21 cats
survived.
Cat, 5 treated with
free nicotine and 3
treated with nicotine
sulphate, sex not
specified
Nicotine
caused CNS
effects and
vomiting, loss
of
consciousness
and death.
Faulkner, 1933
No effects
were reported
with the
sulphate.
June 2014
In this instance, Test data on the mixture as a whole are not available, nor are there Sufficient data available
on similar mixtures. However, there are Available data for all ingredients, allowing classification by applying
the formula in section 3.1.3.6.1.
Section 3.1.3.6. Classification of mixtures based on ingredients of the mixture (Additivity formula)
provides guidance on such classification.
June 2014
In the current exercise, bibra was told to assume that the non-nicotine ingredients of the mixtures are
not acutely toxic, and nicotine is the only ingredient with a known acute toxicity.
CLP Category
3
3
4
Not classified
CLP Category
1
2
3
4
Not classified
June 2014
NOTE
This bibra proposal focuses on the classification of mixtures, accepting the literature LD50 figures and
the existing classification views of the harmonised experts. It did not attempt to critically evaluate the
reliability of the actual LD50 figures. It is possible that a critical evaluation of the existing LD50
literature might lead to a more confident identification of the best LD50 figures to use in substance
and mixture classification.
REFERENCES
ACGIH (2001). Documentation of the threshold limit values for chemical substances. 7th Edition.
American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio.
Arena J (1974). Poisoning IV Ed. New York Charles Thomas Ed. (cited in IPCS, 1991).
DECOS (2004). Nicotine. Health-based Reassessment of Administrative Occupational Exposure Limits.
Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits, The
Hague. 2000/15OSH/105. March 30 2004. http://www.gr.nl/pdf.php?ID=954&p=1
Faulkner JM (1933). Nicotine poisoning by absorption through the skin. Journal of the American
Medical Association, 100, 1664-1665.
Gaines T (1960). The acute toxicity of pesticides to rats. Toxicology and Applied Pharmacology, 2,
88-99.
Gosselin RE (1988). Clinical toxicology of Commercial Products. VI. Baltimore, Williams & Wilkins:
311-313 (cited in IPCS, 1991).
Guerriero FJ, Seaman CW, Sprague GL, Sutton TJ, Allen DJ and Spriggs TL (2001). Acute dermal toxicity
of a nicotine mixture. Toxicologist, 60, 59.
IPCS (1991). Nicotine. PIM. International Programme on Chemical Safety, WHO, Geneva.
http://www.inchem.org/documents/pims/chemical/nicotine.htm
Lazutka FA, Vasilyauskene AD and Gefen SG (1969). Toxicological evaluation of the insecticide nicotine
sulfate. Gig. Sanit, 34(5), 30-33 (cited in ACGIH, 2001; NIOSH, 1996; NIWL, 2005).
NIOSH (1996). Nicotine. IDLH Documentation. The National Institute for Occupational Safety and
Health. http://www.cdc.gov/niosh/idlh/54115.html
NIWL (2005). Consensus report for nicotine. Scientific Basis for Swedish Occupational Standards xxv.
No. 2005:7. Edited by Johan Montelius, Criteria Group for Occupational Standards, National Institute
for Working Life, S-113 91 Stockholm, Sweden.
Sine C (1993). Nicotine. In: Farm chemicals handbook '93, p. C245 (cited in NIOSH, 1996).
Travell J (1960). Absorption of nicotine from various sites. Annals of the New York Academy of
Sciences, 90, 13-30.
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June 2014
Trochimowicz HJ, Kennedy GL Jr and Krivanek ND (1994). Heterocyclic and miscellaneous nitrogen
compounds. In: Clayton GD and Clayton FE, ed. Patty's Industrial Hygiene and Toxicology, 4th ed. John
Wiley & Sons, Inc. New York. IIE, 3374-3379, 3489-3491 (cited in DECOS, 2004).
UK PSD (2008). Draft assessment report. Initial risk assessment provided by the rapporteur Member
State the United Kingdom for the existing active substance nicotine of the fourth stage of the review
programme referred to in Article 8(2) of Council Directive 91/414/EEC. Volume 1 and Volume 3,
Annex B, part 2, B.6. March 2008. Rapporteur Member State assessment reports submitted for the EU
peer review of active substances used in plant protection products. Via http://dar.efsa.europa.eu/darweb/provision
Vernot EH, MacEwen JD, Haun CC and Kinkead ER (1977). Acute toxicity and skin corrosion data for
some organic and inorganic compounds and aqueous solutions. Toxicology and Applied
Pharmacology, 42, 417-423.
Yam J, Reer PJ and Bruce RD (1991). Comparison of the up-and-down method and the fixed-dose
procedure for acute oral toxicity testing. Food and Chemical Toxicology, 29, 259-263.
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June 2014